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3D Structures of Biological Macromolecules Part 3: Drug Research and Design. Jürgen Sühnel jsuehnel@fli-leibniz.de. Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena Centre for Bioinformatics Jena / Germany. Supplementary Material: www.fli-leibniz.de/www_bioc/3D/.
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3D Structures of Biological Macromolecules Part 3: Drug Research and Design Jürgen Sühnel jsuehnel@fli-leibniz.de Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena Centre for Bioinformatics Jena / Germany Supplementary Material: www.fli-leibniz.de/www_bioc/3D/
Example of Drug Discovery Pacific yew tree (Eibe)
Drug Research is the Search for a Needle in a Haystack. www.kubinyi.de
Development of Drug Research www.kubinyi.de
Drug Timeline www.kubinyi.de
Drug Timeline www.kubinyi.de
Costs in Drug Research • Cost for discovering and developing a new drug:several € 100 million up to € 1000 million (average € 802 M) • Time to market: 10 – 15 years
Pharma Sales and Earnings in 1999 - 2002 ww.kubinyi.de
Disciplines Involved in Drug Development Molecular Conceptor
The Role of Molecular Structure Molecular Conceptor
The Pharmacophore Concept Molecular Conceptor
Mechanisms of Drug Action – Definitions I www.kubinyi.de
Mechanisms of Drug Action – Definitions II www.kubinyi.de
Serendipity - Penicillin Molecular Conceptor
Serendipity - Aspirin Serendipity - Aspirin Molecular Conceptor
Strategies in Drug Design www.kubinyi.de
Computational Approaches to Drug Research • Target identification • Lead discovery • Lead optimization • Ligand-based design • Receptor-based design (Docking) • Database screening (Virtual screening) • Supporting combinatorial chemistry
3D Structures in Drug Design www.kubinyi.de
Lead Structure Identification www.kubinyi.de
Lead Structure Search Pipeline www.kubinyi.de
Lead Structures: Endogenous Neurotransmitters voluntary www.kubinyi.de
Lead Structures: Endogenous Neurotransmitters Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between a neuron and another cell. Acetylcholine: voluntary movement of the muscles Noradrenaline: wakefulness or arousal Dopamine: voluntary movement and emotional arousal Serotonin: sleep and temperature regulation GABA: (gamma aminobutryic acid) - motor behaviour www.kubinyi.de
Lead Optimization www.kubinyi.de
Ligand-based Design: QSAR Hansch analysis is the investigation of the quantitative relationship between the biological activity of a series of compounds and their physicochemical substituent or global parameters representing hydrophobic, electronic, steric and other effects using multiple regression correlation methodology. www.kubinyi.de
Ligand-based Design: QSAR Parameters www.kubinyi.de
Ligand-based Design: QSAR Parameters www.kubinyi.de
Ligand-based Design: QSAR Parameters www.kubinyi.de
Ligand-based Design: QSAR Parameters www.kubinyi.de
Ligand-based Design: QSAR Parameters www.kubinyi.de
Ligand-based Design: QSAR Parameters www.kubinyi.de
Ligand-based Design: QSAR Parameters www.kubinyi.de
Ligand-based Design: A QSAR Success Story www.kubinyi.de
Ligand-based Design: A QSAR Success Story pI50 – concentration of test compound required to reduce the protein content of cell by 50% www.kubinyi.de
Ligand-based Design: 3D-QSAR CoMFA www.kubinyi.de
Molecular Superposition of D Receptor Ligands www.kubinyi.de
Ligand-based Design: 3D-QSAR CoMFA www.kubinyi.de
Ligand-based Design: 3D-QSAR CoMFA www.kubinyi.de
Ligand-based Design: 3D-QSAR CoMFA Comparative Molecular Field Analysis
Receptor-based Design (Structure-based Design) Molecular Conceptor
Receptor-based Design (Structure-based Design) Molecular Conceptor
Receptor-based Design: Docking Molecular Conceptor
Receptor-based Design: Docking Molecular Conceptor
